circadian neuroscience

Brains biological clock stimulates thirst before sleep

The brain’s biological clock stimulates thirst in the hours before sleep, according to a study published in the journal Nature by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC).

The finding – along with the discovery of the molecular process behind it – provides the first insight into how the clock regulates a physiological function. And while the research was conducted in mice, “the findings could point the way toward drugs that target receptors implicated in problems that people experience from shift work or jet lag,” says the study’s senior author, Charles Bourque, a professor in McGill’s Department of Neurology and scientist at the Brain Repair and Integrative Neuroscience Program at the (RI-MUHC).

Scientists knew that rodents show a surge in water intake during the last two hours before sleep. The study by Bourque’s group revealed that this behavior is not motivated by any physiological reason, such as dehydration. So if they don’t need to drink water, why do they?

The team of researchers, which included lead author and Ph.D. student Claire Gizowski, found that restricting the access of mice to water during the surge period resulted in significant dehydration towards the end of the sleep cycle. So the increase in water intake before sleep is a preemptive strike that guards against dehydration and serves to keep the animal healthy and properly hydrated.

Then the researchers looked for the mechanism that sets this thirst response in motion. It’s well established that the brain harbors a hydration sensor with thirst neurons in that sensor organ. So they wondered if the SCN (suprachiasmatic nuclei), the brain region that regulates circadian cycles – a.k.a. the biological clock – could be communicating with the thirst neurons.

The team suspected that vasopressin, a neuropeptide produced by the SCN, might play a critical role. To confirm that, they used so-called “sniffer cells” designed to fluoresce in the presence of vasopressin. When they applied these cells to rodent brain tissue and then electrically stimulated the SCN, Bourque says, “We saw a big increase in the output of the sniffer cells, indicating that vasopressin is being released in that area as a result of stimulating the clock.”

To explore if vasopressin was stimulating thirst neurons, the researchers employed optogenetics, a cutting-edge technique that uses laser light to turn neurons on or off. Using genetically engineered mice whose vasopressin neurons contain a light activated molecule, the researchers were able to show that vasopressin does, indeed, turn on thirst neurons.

“Although this study was performed in rodents, it points toward an explanation as to why we often experience thirst and ingest liquids such as water or milk before bedtime,” Bourque says. “More importantly, this advance in our understanding of how the clock executes a circadian rhythm has applications in situations such as jet lag and shift work. All our organs follow a circadian rhythm, which helps optimize how they function. Shift work forces people out of their natural rhythms, which can have repercussions on health. Knowing how the clock works gives us more potential to actually do something about it.”

Finding the body clock’s molecular reset button

In a study published online April 27 in Nature Neuroscience, the authors, led by researchers at McGill and Concordia universities in Montreal, report that the body’s clock is reset when a phosphate combines with a key protein in the brain. This process, known as phosphorylation, is triggered by light. In effect, light stimulates the synthesis of specific proteins called Period proteins that play a pivotal role in clock resetting, thereby synchronizing the clock’s rhythm with daily environmental cycles.

Shedding light on circadian rhythms

“This study is the first to reveal a mechanism that explains how light regulates protein synthesis in the brain, and how this affects the function of the circadian clock,” says senior author Nahum Sonenberg, a professor in McGill’s Department of Biochemistry.

In order to study the brain clock’s mechanism, the researchers mutated the protein known as eIF4E in the brain of a lab mouse so that it could not be phosphorylated. Since all mammals have similar brain clocks, experiments with the mice give an idea of what would happen if the function of this protein were blocked in humans.

Running against the clock

The mice were housed in cages equipped with running wheels. By recording and analyzing the animals’ running activity, the scientists were able to study the rhythms of the circadian clock in the mutant mice.

The upshot: the clock of mutant mice responded less efficiently than normal mice to the resetting effect of light. The mutants were unable to synchronize their body clocks to a series of challenging light/dark cycles – for example, 10.5 hours of light followed by 10.5 hours of dark, instead of the 12-hour cycles to which laboratory mice are usually exposed.

“While we can’t predict a timeline for these findings to be translated into clinical use, our study opens a new window to manipulate the functions of the circadian clock,” says Ruifeng Cao, a postdoctoral fellow in Dr. Sonenberg’s research group and lead author of the study.

For co-author Shimon Amir, professor in Concordia’s Department of Psychology, the research could open a path to target the problem at its very source. “Disruption of the circadian rhythm is sometimes unavoidable but it can lead to serious consequences. This research is really about the importance of the circadian rhythm to our general well-being. We’ve taken an important step towards being able to reset our internal clocks — and improve the health of thousands as a result.”